Bis-(para-tertiary aminoalkoxy-halogenophenyl)-cycloalkanes



United States Patent 3,340,301 BIS-(PARA-TERTIARY AMINOALKOXY-HALO- GENOPHENYIJ-CYCLOALKANES Adrian Marxer, Muttenz, Alan Francis Thomas, Vernier- Geneva, and Atso Ilvespaa, Neuallschwil, Switzerland, assignors to Ciba Corporation, New York, N.Y., a corporation of Delaware No Drawing. Filed Sept. 29, 1965, Ser. No. 491,442 Claims priority, application Switzerland, Jan. 27, 1961, 995/ 61; Dec. 6, 1961, 14,150/ 61 Claims. (Cl. 260570) This is a continuation-in-part of our copending applica tion, Ser. No. 168,542, filed Jan. 24, 1962, now US. Patent No. 3,247,199.

The present invention provides dialkyl-bis-(para-tertiary aminoalkoxy-halogenophenyl)-methanes in which the alkyl groups at the methylene group may be linked together, and their salts, and a process for preparing same.

In the new compounds the alkyl radicals attached to the methylene group may be identical or different from one another and represent preferably lower alkyl groups with l to 5 carbon atoms, such as methyl, ethyl, propyl, isopropyl, or straight or branched butyl or pentyl groups which may be bound in any desired position.

When the alkyl radicals are linked, they together form an alkylene radical, for example a lower alkylene radical, such as a tetramethylene or pentamethylene radical.

The alkylene radicals, which in the tertiary aminoalkoxy-halogenophenyl groupings link the tertiary amino groups to the oxygen atoms, are preferably unbranched or branched lower alkylene groups with 2 to 5 carbon atoms, which separate the tertiary amino group from the oxygen atom 'by at least 2 carbon atoms, such as ethylene groups, or unbranched or branched propylene, butylene or pentylene groups.

The phenylene radicals contain especially 1 to 2 halogen atoms each. The halogen atoms are preferably chlorine or bromine atoms and are advantageously in orthoposition to the tertiary aminoalkoxy group.

As substituents of the tertiary amino group there are particularly suitable lower hydrocarbon radicals which may be interrupted by hetero atoms, such as oxygen, sulfur or nitrogen, and may be bound to the alkylene radical, and/or they may be substituted by free hydroxyl, amino or mercapto groups or by halogen atoms, such as fluorine, chlorine or bromine. Particularly suitable lower hydrocarbon radicals are: lower alkyl or alkenyl radicals, such as methyl, ethyl, propyl, isopropyl, or unbranched or branched groups, linked in any desired position, including butyl, pentyl, hexyl or heptyl radicals, allyl or methallyl radicals, unsubstituted or alkylated cycloalkyl or cycloalkenyl groups such as cyclopentyl, cyclohexyl, cycloheptyl, cyclopentenyl or cyclohexenyl radicals; unsubstituted or alkylated cycloalkylor cycloalkenyl-alkyl groups such as cyclopentylor cyclohexenyl-methyl, -ethyl or -propyl radicals; aralkyl or aralkenyl such as phenylmethy1-, -ethyl, -vinyl or propyl groups, or alkylene or alkenylene radicals such, for example as 1:4-butylene, 1:5-pentylene, 1:S-dimethylpentylene-(lzS), 1:6-hexylene or 1:5- hexylene. Radicals of this type that are interrupted by heteroatoms are, for example, alkoxyalkyl or oxa-cycloalkyl-alkyl radicals, such as methoxyethyl, ethoxyethyl, propoxyethyl, butoxyethyl, methoxypropyl, methoxy- 3,340g30 l Patented Sept. 5, 1967 ethoxyethyl, tetrahydrofurylmethyl, methylmercaptoethyl, oxa-, azaor thia-alkyleneor -alkenylene radicals such as 2-azabutene-( 1:2)-ylene-( 1:4), 2-aza, oxa, or thiabutylene-( 1 :4) groups, 2-aza-pentene-(1 :2)-ylene-(1 :5) 3-aza-, oxaor thia-pentylene-(1:5 3-azahexylene(1:6), 1:5 dimethyl-3-azapentylene-(1:5), 3-methyl-3-aza-pentylene 1 :5) or 3-hydroxyethyl-3 -azapentylene-( 1 :5 Tertiary aminoalkoxy radicals, in which a substituent of the tertiary amino group is linked with the alkylene radical, or for example N-alkyl-pyrrolidinyl-Z- or -3-alkoxy radicals or N-alkyl-piperidyl-2-or -3-alkoxy radicals.

The amine group is primarily a di-lower alkylamino group such as the dimethylamino, diethylamino, dipropylamino, N-methyl-N-ethylamino group, an N-lower alkyl- N-cycloalkylamino group such as the N-methyl-N-cyclopentyl or -cyclohexyl group, or a pyrrolidino, piperidino, morpholino or thia-morpholino group such as the pyrrolidino, piperidino, morpholino, piperazino or N-methylpiperazino group.

The new compounds possess valuable pharmacological properties. Inter alia, they display an antipyretic, analgesic and anti-inflammatory action. More especially they have an antiparasitic, such as an amoebicidal and trypanocidal action, which enables them to be used pharmacologically or as medicaments. They are also useful as intermediate products for the preparation of medicaments.

Of special value are the compounds of the formula where n=2 or 3; Hal stands for chlorine or bromine and A for chlorine, bromine or hydrogen, and R to R represent lower alkyl radicals, or R and R together with the nitrogen atom and/or R and R together with the nitrogen atom, may also represent an alkyleneimino ring which may be interrupted by hetero atoms as specified aboveand their salts, and the compounds of the formula H2O OH: I R Hal I 1 Hal Hz C\ CH2 in which Hal, A, n R to R have the meaning given above, and salts of these compounds.

The new compounds are obtained in known manner; preferably, a reactive ester of a tertiary aminoalkanol is reacted upon a compound of the formula wherein R and R represent alkyl groups which may be linked together and the symbols Ph represent halogenated para-phenylene radicalspreferably in the form of a metal salt thereof such, for example, as an alkali metal salt, or in the presence of a condensing agent forming such asalt. Reactive. esters are, for example, those with strong inorganic or organic acids, preferably those of hydrohalic acids such as hydrochloric, hydrobromic or hydriodic acid, or of arylsulfonic acids, such as benzenesulfonic or toluenesulfonic acid.

The afore-mentioned reaction is performed in a manner known per se, in the presence or absence of a diluent, at room temperature or a lower or higher temperature, under atmospheric or superatmospheric pressure.

Depending on the reaction conditions used, the new compounds are obtained in the form of the free bases or of their salts. From the salts the free amine bases can be prepared in the known manner. From the amine bases, on the other hand, salts can be prepared by treatment with acids that yield therapeutically useful salts, such, for

example, as a hydrohalic acid, sulfuric, nitric, phosphoric, thiocyanic, acetic, propionic, oxalic, malonic, tartaric, succinic, malic, methanes'ulfonic, ethanesulfonic, hydroxyethanesulfonic, benzenesulfonic or toluenesulfonic acid, or other therapeutically acceptable acids.

The salts of the new compounds may also be used for purifying the bases obtained, for example, by converting a base into a salt thereof, separating the latter and reconvertiug it into the base.

The starting materials are known or can be made by known methods.

The invention includes also any variant of the present process in which an intermediate obtained at any stage thereof is used as starting material and the remaining step or steps is/are carried out, or the process is discontinued at any stage thereof, or the starting materials are 2 formed under the reaction conditions. For example, a

corresponding dialkyl-(para-tertiary-aminoalkoxy halogenphenyl)-(para-hydroxy-halogenphenyl)-methane, may be reacted with a reactive ester of a tertiary aminoalkanol.

In this way; for example, compounds may be obtained in which the two tertiary amino groups are not identical.

The new compounds can be used as medicaments, for example in the form of pharmaceutical preparations containing them or their salts in admixture with an organic or inorganic, solid or liquid pharmaceutical excipient suitable for enteral, local or parenteral administration. Suitable excipients are substances that do not react with the new compounds such, for example, as water, gelatine, lactose, starches, magnesium stearate, talc, vegetable oils, benzyl alcohols, gums, polyalkylene glycols, white petroleum jelly, cholesterol or other known medicinal excipients. The pharmaceutical preparations may be, for example, tablets, drages, ointments or creams, or in liquid forms solutions, suspensions or emulsions. They may be sterilized and/or may contain assistants such as preserving, stabilizing, wetting or emulsifying agents, salts for regulating the osmotic pressure, buffers and/or solution promoters. They may also contain further therapeutically valuable substances. The preparations are formulated by conventional methods.

The following examples illustrate the invention:

Example 1 A solution of 2.3 grams of sodium in 100 cc. of ethanol is treated with 19 grams of dimethyl-bis-[3-bromo- 4-hydroxyphenyl]-methane in 200 cc. of ethanol. A solution of 15 grams of B-diethylamino-ethylchloride in 70 cc. of benzene is then added dropwise, and the whole is refluxed for 2 hours, cooled, filtered and evaporated to dryness in vacuo. .The residue is dissolved in a mixture of 300 cc. of ether and 100 cc. of ethyl acetate, and the is extracted with 2 N-hydrochloric acid. The hydrochloric acid extract is alkalinized with 10 N-sodium hydroxide solution, the precipitated base is again taken up in ether-i-ethyl acetate, dried with sodium sulfate, and the solvents are evaporated. The residue is dissolved in cc. of alcohol and treated with a concentrated solution of 19 grams of citric acid in ethanol. The resulting crystalline dicitrate is filtered oil and recrystallized from alcohol. It melts at 129131 C.

Example 2 I I Br Br is extracted with 200 cc. of 2 N-hydrochloric acid. The hydrochloric acid extract is neutralized with 200 cc. of 2 N-sodium hydroxide solution, the precipitated base is once more taken up in ether-l-ethyl acetate, then dried with sodium sulfate, and the solvents are evaporated. The monocitrate melts at 125127 C. (from alcohol).

The resulting dimethyl-[3-bromo-4-(fl-diethylaminoethoxy) -phenyl] -3 -bromo-4'-hydroxy-phenyl] -methane is reacted in a manner analogous to that described above with 15 grams of fl-diethylaminoethyl chloride dissolved in cc. of benzene and worked up as described in Example 1, to yield dimethyl-bis-[3-b-romo-4-(fi-diethylamino-ethoxy)-phenyl] -methane-dicitrate which is identical with the dicitrate described in Example 1.

Example 3 19.2 grams of solid dimethyl-bis-[3-bromo-4-hydroxyphenyl]-methane are stirred into a solution of 2.3 grams of sodium in 200 cc. of ethanol.

A solution of 18.5 grams of B-dimethylamino-ethylchloride hydrochloride in 25 cc. of water is mixed with 35 cc. of a concentrated solution of potassium carbonate. The precipitated chlorine base is taken up in cc. of benzene, the benzene solution is dried and added dropwise to the solution of the diphenylmethane derivative.

The mixture is refluxed for 3 hours, then filtered, concentrated to about one third of its volume, and the concentrate is treated with 50 cc. of 2 N-alcoholic hydrochloric acid, to yield the dihydrochloride of dimethyl-bis-[3- bromo-4 (p-dimethylaminoethoxy) -phenyl] -methane of the formula resulting dimethyl bis-[3-bromo-4-(p-diethylamino-ethoxy) -phenyl] -methane of the formula which melts at 201 C. after recrystallization from isopropanol.

3,340,301 5 V v 6 7 Example 4 hydrochloric acid. By adding ether the dihydrochloride of dimethyl-bis-[3-chloro 4 ('y dimethylamino-propoxy)- A solution of 2.3 grams of sodium in 200 cc. of ethanol phenynmmthane of the formula is treated with 19.2 grams of dimethy1-bis-[3-bromo-4- hydroxyphenyl] -methane. From 21 grams of 'y-dimethylis caused to precipitate; after recrystallization from isoaminopropylchloride hydrochloride the base is liberated propanol it melts at 197-198 C.

as described in Example 3, taken up in benzene and added E l 7 dropwise at room temperature to the solution of diphenylxamp e methane; the mixture is boiled for 3 hours, then filtered By the method described in Example 6 the base is and evaporated. The residue is dissolved in 100 cc. of a 15 liberated from 18.5 grams of S-dimethylamino-ehtylchlo- 1: l-mixture of alcohol and ether and treated with 50 cc. ride hydrochloride, then dissolved in benzene and added of 2 N-alcoholic hydrochloric acid. The dihydrochloride dropwise to a solution prepared in the following manner: of dimethyl-bis-[3-bromo-4-(y-dimethylaminopropoxfi- A solution of 2.3 grams of sodium in 100 cc. of ethanol pheny11-methane of the formula is treated with 18.3 grams of dimethyl-bis-[3z5-dichloro- Br Br is precipitated with ether and recrystallized from iso- 4-hydroxyphenylJ-methane. The mixture is refluxed for 3 propan-ol. It melts at 206 C. hours, then filtered and evaporated to dryness in vacuo.

Example 5 The crystalline base is dissolved in alcohol and converted with 50 cc. of 2 N-alcoholic hydrochloride into the di- A solution of 2.3 grams of sodium in 200 cc. of alcohol h d hl id of di l bi 3;5-di h1 -4- -di. is leaded with grams of y ls-[3-ChIO O-4- methylamino-ethoxy)-phenyl]-methane of the formula hydroxyphenyll-methane as described in Example fl, and which, on addition of ether crystallizes, and after rethe resulting di-sodium salt 1s treated dropwise with 15 crystallization from a mixture of isopropanol and ethyl grams of fi-diethylamino-ethylchloride in 70 cc. of bent te lts 1; 220 c, zene. The mixture is refluxed for 3 hours, then filtered and E v l 8 evaporated in vacuo. The residue is dissolved in cc. xamp e of alcohol, treated with 19 grams of citric acid, and 2.3 grams of sodium in 100 cc.'of ethanol, 10.3 grams the dicitrate of dimethyl-bis-[3-chloI'o-4-(B-diethylaminoof dimethyl-bis[3:5-dichloro-4-hydroxyphenyl] -methane ethoxy)-phenyl]-methane of the formula and 15 grams of fi-diethylamino-ethylchloride in cc.

CH3 (C Hs)2N-OH=OH -O-+OCH CH N(CzH -Dicitrate I CH: 01

is caused to crystallize out by the addition of ether. After of benzene are reacted as described in Example 1, and recrystallization from ethanol of strength it melts 50 the resulting dimethyl bis [3:5-dichloro-4-(fl-diethylat 149-150" C. amino-ethoxy) -phenyl)-methane of the formula I (C2115)zNCHzOHz0@?OCHz-CH:N(O HQ QHCI OH ('11 3 (51 Example 6 is converted into the dihydrochloride which, after re- A solution of 23 grams of Sodium in of crystalization form isopropanol-l-ether, melts at 207- ethanol is treated with 15 grams of dimethyl-bis-[3- 60 208 chloro-4-hydroxyphenyl]-methane. A benzolic dimethyl- Example 9 amino-propylchloride solution is prepared by reacting a solution of 21 grams of 'y-dimethylamino-propylchloride grams of Sodium 100 of ethanol grams hydrochloride in 25 cc. of Water with 50 cc. of concenof dimethY'I'biSBi5jdichloro'4jhydroxyphenyl]methane trated potassium carbonate solution and taking up the 65 and 21 grams of 'Y' l -p Y reaction product i 150 of benzene, d h Stirred chloride are reacted and worked up by the method dedropwise at room temperature into the above-described scribed in Examples 6 and 1 and the resulting dimethylsolution of the di-sodium salt. The whole is refluxed for his [3:5-dichloro-4-(' dimethylamino-propoxy)-phenyl]- 3 hours, filtered and treated with 50 cc. of 2 N-alcoholic methane of the formula I (CH3) 2NCH2-CH2CH2O filQO-OHPOHPOHi-N CH3) 1 CE: V 01 01 7 8 is converted into the dihydrochloride which, on recrystaladded in one portion to a solution of 4.6 grams of solization from a mixture of isopropanol and ethyl acetate, dium in 200 cc. of absolute alcohol. 18.6 grams of mormelts at 232 C. pholinoethyl chloride hydrochloride are then added, the Example reaction mixture stirred under reflux for 6 hours and left 5 to stand at room temperature overnight. The crystalline A solution of 2.3 grams of sodium in 100 cc. of absoprecipitate is suction-filtered, washed first with alcohol,

lute alcohol is mixed with a solution of 27.2 grams of dithen with water and dried to yield dimethyl-bis-[BzS-dimethyl y yp y l han in bromo-4-(morpholino-ethoxy)-phenyl]-methane of the 200 cc. of absolute alcohol. In the course of 5 minutes form l Br Br I OH: 5 l f N-OHs-CHr-O C O-GHz-CHr-N O I C 3 Br Br 14.9 grams of ,3-diethylamino-ethylchloride in 50 cc. of melting at 120-l22 C.

absolute benzene are then added dropwise and the reac- For conversion into the dihydrochloride the base is ti-on mixture is stirred and refluxed for 6 hours and then dissolved in 50' cc. of absolute alcohol which contains the allowedto cool. The precipitated sodium chloride is filcalculated quantity of hydrochloric acid gas; After a tered off, and the mother liquor is evaporated to dryness. short time the dihydrochloride begins to precipitate. It is The oily residue is taken up in ether, extracted by being suction-filtered, washed with alcohol and dried. The prodshaken twice with 2 N-sodium hydroxide solution, dried uct melts at 206-207 C.

with sodium sulfate and converted with alcoholic hydro- Exam 13 chloric acid into the dihydrochloride of dimethyl-bisp [3:5 -.dibromo-4-(B diethyl-amino-ethoxy)-phenyl1-meth- A solution of 19.3 grams of ,8:,8-bis-(3-bromo-4-hy.- ane of the formula droxy-phenyl)-propane in 100 cc. of absolute alcohol is Br 3 Br 7 (17H: l (OzHshN-OHz-GHy-OQC-QOCHaCHzN(OzHs)z.2HC1

| CH: Br Br which settles out and, after recrystallization from isoadded in one portion to a solution of 4.6 grams of sodium propanol-i-ethyl acetate, melts at 208209 C. with dein 200 cc. of absolute alcohol. 18.6 grams of morpholinocomposition. ethyl chloride hydrochloride are then added, the reaction Example 11 mixture stirred for 6 hours under reflux and left to stand at room temperature overnight. The precipitated sodium A solution of 4.8 grams of sodium in 200 cc. of absochloride is filtered off and the alcoholic mother liquor lute alcohol is mixed with a solution of 27.2 grams of evaporated to dryness to yield dimethyl-bis-[3-bromo-4- dimethyl bis-[3 :5-dibromo-4-hydroxyphenyl] -methane in (morpholino-ethoxy)-phenyl] -methane of the formula 200 cc. of absolute alcohol. 20.47 grams of -diethylas a viscous oil.

amino-propylchloride hydrochloride are then added and By dissolving the oil in 100' cc. of ethyl acetate and the reaction mixture is refluxed and stirred for 6 hours, adding the calculated quantity of alcoholic hydrochloric and then allowed to cool. The precipitated sodium chloacid, the product may be converted into the dihydrochloride is filtered off, and the mother liquor is evaporated to ride which melts at 234237 C.

dryness. The residue is boiled for a short time with 100 7 cc. of ethyl acetate, filtered, treated with 50 cc. of 2.45 Example 14 N-alcoholic hydrochloric acid and evaporated to dryness. I The oily residue is dissolved in a small amount of iso- A 5011mm 0f grams of 1 propanol and ethyl acetate is added until crystallization -p y ly in 100 f lu e alcohol sets in. After one hour the precipitated dimethyl-bis-[3:5- 0 is added in one PQIfiOH a Solution of grams of dibromo 4- ('y-diethylaminopropoxy)-phe 1]-m th sodium in 100 cc. of absolute alcohol. 13.9 grams of dihydrochloride of the formula chlorethyldiethylamine dissolved in 50 cc. of absolute 'is suctioned off, washed with ethyl acetate and dried. It 70 benzene are thenadded dropwise in the course of about melts t 205-206 C, 10 minutes, with stirring, to the reaction solution. Stirring is continued for 6 hours under reflux, the reaction mixture allowed to stand overnight, the precipitated so- A solution of 27.2 grams of SzB-bis-(3z5-dib-romo-4- dium chloride filtered 0E and the alcoholic filtrate evapohydroxy-pheny1)-propane in200 cc. of absolute alcoholis rated to dryness to yield penta-met-hylene-bis-[3:5-di- Example 12 chloro 4-(diethylaminoethoxy)-phenyl]-methane of the formula are members selected from the group consitsin g of lower alkyl, lower alkenyl, cyclo-lower alkyl, cycle-lower al- I H O CE: G1 01 E20 CH1 as an almost colorless, viscous oil.

By dissolving the product in 100 cc. of absolute alcohol and adding an alcoholic solution of the calculated quantity of citric acid, it is converted into the dicitrate melting at 125126 C.

Example By the process described in the preceding example and using 2.17 grams of sodium, 15.9 grams of 1:1-bis-(3- ch1oro-4-hydr0Xy-phenyl)-cyclohexane and 12.8 grams of chlorethyldiethylamine, there is obtained penta-methylenebis [3-chloro-4-(diethylamino-ethoxy)-phenyl]-methane of the formula kenyl, phenyl-lower alky'l, N,N-lower alkylene, N ,N-mo-no- 1 doXa-lower alkylene, N,N-mono-aza-lower alkylene and N,N-mono-thia-lower alkylene, R and R each stands for a member selected from the group consitsing of hydrogen, chlorine and bromine, and A and A each stands for lower alkylene having from 2 to 5 carbon atoms and separating tertiary amino from on by at least two carbon atoms, halogen stands for chlorine and bromine and acid addition salts thereof.

2. A member selected from the group consisting of a compound of the formula The dicitrate of this base melts at 121-123" C.

Example 16 in which n, p and m each stands for an integer from 2 to 3, Hal and Hal each stands for a member selected tion mixture is stirred and refluxed for 6 hours. After from the group consisting of chlorine and bromine, R

cooling, the precipitated sodium chloride is filtered off, and the mother liquor evaporated to dryness. The oily residue is dissolved in 200 ml. of ethyl acetate, freed from a slight turbidity by filtration, and the solution then treated with 40 ml. of 2.4 N-alcoholic hydrochloric acid. The pentamethylene bis[3 :5-dibromo-4-(B-diethylaminoethoXy)-phenyl]]-methane dihydrochloride of the formula Br Br and R each stands for a member selected from the group consisting of chlorine, bromine and hydrogen, R and R stand for a member selected from the group consisting of lower alkyl, and, when taken together, lower alkylene, mono-oxa-lower alkylene, mono-aza-lower alkylene and mono-thia-lower alkylene, and R and R stand for a member selected from the group consisting of lower alkyl,

C2335 CH2 C 2 Br I 1 Br CH1 CH2 precipitates and is recrystallized from acetonitrile. Melting point, 208-210 C. (with decomposition).

What is claimed is:

1. A member selected from the group consisting of compounds of the formula raogen halogen in which R stands for lower alkylene, R and R each 0 3 :5-dibromophenyl1-methane.

No references cited.

CHARLES B. PARKER, Primary Examiner.

stands for a tertiary amino group in which the substituents R. V. HINES, Assistant Examiner. 

1. A MEMBER SELECTED FROM THE GROUP CONSISTING OF COMPOUNDS OF THE FORMULA 